Soluble HER2 ECD Decoy for Antibody Neutralization

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Solution Overview

Problem

Current therapies for breast cancer, particularly those targeting HER2-positive breast cancer, face limitations such as restricted inhibition to cell surface HER2, neutralization by circulating extracellular domains, and development of acquired resistance, necessitating the development of more effective anti-HER2 agents.

Innovation Solution

The development of a soluble, pegylated human epidermal growth factor receptor-2 (HER2) protein lacking the region encoded by exon 15 and a corresponding coding sequence, as well as splice-switching oligonucleotides, to inhibit full-length HER2 protein and modulate its expression, thereby treating HER2-positive breast and ovarian cancers.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If Herceptin is used to target HER2, then HER2 signaling is inhibited, but circulating ECDs neutralize the antibody and reduce efficacy

Engineering Contradiction:

ImproveHER2 inhibition efficacyVSAvoidNeutralization by circulating ECDs

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces a soluble HER2 ECD as an intermediary that preferentially binds to circulating ECDs, preventing them from neutralizing the anti-HER2 antibody. This mediator absorbs the harmful neutralizing effect, protecting the primary therapeutic antibody from inactivation and maintaining its oncology-targeting efficacy

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention converts the harmful effect of circulating ECDs (which neutralize therapy) into a beneficial by providing a decoy ECD that deliberately binds to these circulating ECDs. The harmful neutralizing ECDs are redirected to bind with the soluble ECD instead, transforming them from therapeutic antagonists into controlled binding partners that enhance overall treatment efficacy

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

2Reliability

If Herceptin is administered, then cell surface HER2 is inhibited, but intracellular HER2 remains active for signaling

Engineering Contradiction:

ImproveHER2 signaling inhibitionVSAvoidCoverage of intracellular HER2

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent segments the HER2 receptor into its extracellular domain (soluble ECD) and membrane-bound portions. By administering the soluble ECD segment separately, it creates a dual-action therapy: the antibody component targets cell surface and intracellular HER2, while the soluble ECD component circulates to neutralize soluble HER2 molecules that would otherwise escape antibody detection and signaling

Inventive Principle:

Principle #1Segmentation

3Duration of action of stationary object

If prolonged Herceptin treatment is given, then cancer growth is suppressed, but acquired resistance develops

Engineering Contradiction:

ImproveTreatment durationVSAvoidTherapeutic efficacy

Core Design Contradiction:

Duration of action of stationary objectVSReliability

Solution Approach 1:

The patent applies preliminary action by co-administering the soluble HER2 ECD with the anti-HER2 antibody from the start of treatment. This preliminary presence of the soluble ECD prevents the development of resistance mechanisms by continuously neutralizing soluble HER2 and modulating the tumor microenvironment, thereby maintaining therapeutic efficacy throughout prolonged treatment periods

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention changes the therapeutic parameter from a single antibody component to a combination of antibody plus soluble ECD. This parameter change creates a more complex therapeutic profile that addresses multiple resistance mechanisms simultaneously, including neutralization of soluble HER2, modulation of tumor microenvironment, and prevention of antibody neutralization, thereby sustaining efficacy over time

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The soluble HER2 protein and oligonucleotides effectively inhibit HER2 signaling, overcoming resistance and providing sustained pharmacokinetic benefits, leading to enhanced treatment efficacy for HER2-positive breast and ovarian cancers.

Implementation Method 1

The soluble form of the HER2 receptor... can be used to treat certain cancers... The soluble HER2 protein and oligonucleotides effectively inhibit HER2 signaling

Methodology Applied

Scientific EffectCompetitive binding:

Implementation Method 2

The protein may be pegylated, that is, derivatized with polyethyleneglycol chains, to improve its pharmacokinetic properties, e.g., circulation time in the blood

Methodology Applied

Scientific EffectPegylation:

Implementation Method 3

splice-switching oligonucleotides, and their use in the treatment of disease... a coding sequence... to inhibit full-length HER2 protein and modulate its expression

Methodology Applied

Scientific EffectAlternative splicing:

Data Source

PatentEP2173373B1Soluble her2 and her3 splice variant proteins, splice-switching oligonucleotides, and their use in the treatment of disease

Publication Date: 2020.04.15 SAREPTA THERAPEUTICS INC

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AI summary

Soluble epidermal growth factor receptors 2 and 3 (HER2 and HER3) splice variant proteins with HER2 and HER3 antagonist activity and anti-proliferative properties, as well as the corresponding nucleic acids, are provided for treatment of proliferative diseases, in particular cancer. Also provided are compositions and methods for inducing expression of these splice variants, including splice switching oligonucleotides that modulate splicing of pre-mRNA that codes for these receptors.